Epacadostat and Sirolimus in Treating Participants with Advanced Cancer

Inclusion Criteria

• DOSE ESCALATION COHORT: Ability to understand and the willingness to sign a written informed consent
• DOSE ESCALATION COHORT: Prior treatment with at least one line of systemic therapy
• DOSE ESCALATION COHORT: Subjects with advanced and unresectable solid tumor who progressed on at least one line of systemic therapy, and no approved therapy or standard therapy with demonstrated clinical benefit exists; and all subjects with T790M mutation positive NSCLC have progressed on osimertinib * Note: disease measurability is not required for dose escalation
• DOSE ESCALATION COHORT: Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• DOSE ESCALATION COHORT: Leukocytes >= 3,000/mcL
• DOSE ESCALATION COHORT: Absolute neutrophil count >= 1,500/mcL
• DOSE ESCALATION COHORT: Platelets >= 100,000/mcL
• DOSE ESCALATION COHORT: Hemoglobin >= 9 g/dL
• DOSE ESCALATION COHORT: Total bilirubin within normal institutional limits
• DOSE ESCALATION COHORT: Aspartate transaminase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 2.5 X institutional upper limit of normal (ULN)
• DOSE ESCALATION COHORT: Alanine transaminase (ALT) (serum glutamic pyruvic transaminase [SPGT]) =< 2.5 X ULN
• DOSE ESCALATION COHORT: Alkaline phosphatase (ALP) =< 2.5 X ULN
• DOSE ESCALATION COHORT: Serum creatinine =< 1.5 X ULN or creatinine clearance (CrCl) >= 50ml/min
• DOSE ESCALATION COHORT: * Note: Subjects with bone metastasis and no liver metastasis on screening image may enroll if ALP is < 5 X ULN; subjects with liver metastasis may enroll if all of AST/ALT/ALP are < 5 X ULN; however, subjects with extensive liver metastasis occupying more than 50% of liver parenchyma will be excluded per epacadostat investigator’s brochure
• DOSE ESCALATION COHORT: Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy, as long as partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
• DOSE ESCALATION COHORT: Women of child-bearing potential and men with partners of child-bearing potential must agree to practice sexual abstinence, or to use two forms of adequate contraception (hormonal AND barrier method of birth control) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy; if a woman becomes pregnant or suspects she is pregnant while participating in this study, she should inform her treating physician immediately * A woman of child-bearing potential is any female (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: ** Has not undergone a hysterectomy or bilateral oophorectomy; or ** Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months) * Men of child-bearing potential must not donate sperm while on this study and for 90 days after their last study treatment; NOTE: acceptable forms of birth control are listed below: ** One barrier method (cervical cap with spermicide plus male condom; diaphragm with spermicide plus male condom) PLUS ** Hormonal method (oral contraceptives, implants, or injections) or an intrauterine device (e.g., Copper-T)
• DOSE EXPANSION COHORT: Ability to understand and the willingness to sign a written informed consent
• DOSE EXPANSION COHORT: Prior treatment with at least one line of systemic therapy
• DOSE EXPANSION COHORT: Subjects with metastatic or recurrent NSCLC who progressed on at least one line of systemic therapy for metastatic or recurrent disease, which must include anti PD-1 or PD-L1 inhibitor, and must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and accessible tumor for biopsy; archived tissue material should be available for baseline immunohistochemistry (IHC) studies; molecular status of EGFR and ALK must have been assessed for nonsquamous NSCLC; those with activating EGFR mutation or ALK gene arrangement must have progressed on at least one kinase inhibitor; patients with EGFR mutation must have had progression on osimertinib
• DOSE EXPANSION COHORT: ECOG performance status 0-2
• DOSE EXPANSION COHORT: Leukocytes >= 3,000/mcL
• DOSE EXPANSION COHORT: Absolute neutrophil count >= 1,500/mcL
• DOSE EXPANSION COHORT: Platelets >= 100,000/mcL
• DOSE EXPANSION COHORT: Hemoglobin >= 9 g/dL
• DOSE EXPANSION COHORT: Total bilirubin within normal institutional limits
• DOSE EXPANSION COHORT: AST(SGOT) =< 2.5 X institutional upper limit of normal (ULN)
• DOSE EXPANSION COHORT: ALT(SPGT) =< 2.5 X ULN
• DOSE EXPANSION COHORT: ALP =< 2.5 X ULN
• DOSE EXPANSION COHORT: Serum creatinine =< 1.5 X ULN or CrCl >= 50 ml/min
• DOSE EXPANSION COHORT: * Note: subjects with bone metastasis and no liver metastasis on screening image may enroll if ALP is < 5 X ULN; subjects with liver metastasis may enroll if all of AST/ALT/ALP are < 5 X ULN; however, subjects with extensive liver metastasis occupying more than 50% of liver parenchyma will be excluded per epacadostat investigator’s brochure
• DOSE EXPANSION COHORT: Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy, as long as PTT is within therapeutic range of intended use of anticoagulants
• DOSE EXPANSION COHORT: Women of child-bearing potential and men with partners of child-bearing potential must agree to practice sexual abstinence, or to use two forms of adequate contraception (hormonal AND barrier method of birth control) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy; if a woman becomes pregnant or suspects she is pregnant while participating in this study, she should inform her treating physician immediately * A woman of child-bearing potential is any female (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: ** Has not undergone a hysterectomy or bilateral oophorectomy; or ** Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months) * Men of child-bearing potential must not donate sperm while on this study and for 90 days after their last study treatment; NOTE: acceptable forms of birth control are listed below: ** One barrier method (cervical cap with spermicide plus male condom; diaphragm with spermicide plus male condom) PLUS ** Hormonal method (oral contraceptives, implants, or injections) or an intrauterine device (e.g., Copper-T)

Exclusion Criteria

• DOSE ESCALATION COHORT: Current or anticipated use of other investigational agents while participating in this study
• DOSE ESCALATION COHORT: Participation in any other study in which receipt of an investigational study drug occurred within 28 days or 5 half-lives (whichever is longer) before first dose
• DOSE ESCALATION COHORT: Subjects who have received an IDO inhibitor; subjects who have received other immune checkpoint inhibitors (e.g. anti-PD-1, anti-PD-L1, and any other treatment targeting T-cell) will be permitted; subjects who have received experimental vaccines or other immune therapies should be discussed with the principal investigator (PI) to confirm eligibility
• DOSE ESCALATION COHORT: Subjects who have received sirolimus, everolimus, temsirolimus, or any other agent for current malignancy that theoretically targets PI3K, AKT and / or mTOR
• DOSE ESCALATION COHORT: Any prior >= grade 3 immune-related adverse event (irAE) while receiving immunotherapy, including anti-CTLA-4 and anti-PD-1/PD-L1 treatment, or any unresolved irAE > grade 1 * Note: Previous immune-related ocular toxicity of any grade is excluded
• DOSE ESCALATION COHORT: Subjects who are receiving an immunosuppressive treatment for any reason, including chronic use of systemic steroid or prednisone equivalent at doses >= 10 mg/day within 14 days prior to the first dose of study treatment; use of inhaled or topical steroids or systemic corticosteroids < 10 mg is permitted
• DOSE ESCALATION COHORT: Subjects who have had prior radiotherapy within 2 weeks of therapy; subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis
• DOSE ESCALATION COHORT: Patient has received chemotherapy within 3 weeks prior to entering the study or has not recovered sufficiently (i.e., greater than grade 1; PI will judge patient recovery status) from adverse events due to agents administered more than 3 weeks earlier; exceptions are stable chronic toxicities not expected to resolve, such as peripheral neurotoxicity, alopecia, and fatigue
• DOSE ESCALATION COHORT: Prior monoclonal antibody within 4 weeks before study day 1 or not recovered (=< grade 1 or at baseline) from adverse events (AEs) due to agents administered more than 4 weeks earlier; exception to this rule would be use of denosumab
• DOSE ESCALATION COHORT: Brain metastases: symptomatic, unstable, or disease requiring use of steroid treatment
• DOSE ESCALATION COHORT: Subjects with any active or inactive autoimmune process (eg, rheumatoid arthritis, moderate or severe psoriasis, multiple sclerosis, inflammatory bowel disease, etc.) or who are receiving systemic therapy for an autoimmune or inflammatory disease * Exceptions include subjects with vitiligo, hypothyroidism stable on hormone replacement, controlled asthma, type I diabetes, Graves' disease, Hashimoto's disease, or with PI approval
• DOSE ESCALATION COHORT: Evidence of or any history of interstitial lung disease or active, noninfectious pneumonitis including symptomatic and/or pneumonitis requiring treatment
• DOSE ESCALATION COHORT: Hepatitis B virus (HBV) or hepatitis C virus (HCV) viremia or at risk for HBV reactivation; hepatitis B virus deoxyribonucleic acid (DNA) and testing for HCV ribonucleic acid (RNA) must be undetectable; at risk for HBV reactivation is defined as hepatitis B surface antigen positive. Patients who had curative treatment for hepatitis B are allowed in the study
• DOSE ESCALATION COHORT: Subjects with clinical condition where subjects may not tolerate immune mediated hepatotoxicity; this includes extensive liver metastasis, excessive intake of alcohol (male > 4 drinks/day, female > 2 drinks/day), and the use of acetaminophen > 2 gms/day; per epacadostat investigator’s brochure
• DOSE ESCALATION COHORT: History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• DOSE ESCALATION COHORT: Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• DOSE ESCALATION COHORT: Current use or anticipated need for treatment with any medications or substances that are inhibitors or inducers of CYP3A4
• DOSE ESCALATION COHORT: Known allergy or reaction to any component of either study drug formulation; any history of serotonin syndrome (SS) after receiving 1 or more serotonergic drugs
• DOSE ESCALATION COHORT: Pregnant or nursing. There is a potential for congenital abnormalities and for this regimen to harm nursing infants
• DOSE ESCALATION COHORT: Use of any UGT1A9 inhibitor from screening through follow-up period, including the following: diclofenac, imipramine, ketoconazole, mefenamic acid, and probenecid
• DOSE ESCALATION COHORT: Subjects receiving monoamine oxidase Inhibitors (MAOIs) or drug which has significant MAOI activity (meperidine, linezolid, methylene blue) within the 21 days before screening
• DOSE EXPANSION COHORT: Current or anticipated use of other investigational agents while participating in this study
• DOSE EXPANSION COHORT: Participation in any other study in which receipt of an investigational study drug occurred within 28 days or 5 half-lives (whichever is longer) before first dose
• DOSE EXPANSION COHORT: Subjects who have received an IDO inhibitor; subjects who have received other immune checkpoint inhibitors (e.g. anti-PD-1, anti-PD-L1, and any other treatment targeting T-cell) will be permitted; subjects who have received experimental vaccines or other immune therapies should be discussed with the PI to confirm eligibility
• DOSE EXPANSION COHORT: Subjects who have received sirolimus, everolimus, temsirolimus, or any other agent for current malignancy that theoretically targets PI3K, AKT and / or mTOR
• DOSE EXPANSION COHORT: Any prior >= grade 3 immune-related adverse event (irAE) while receiving immunotherapy, including anti-CTLA-4 and anti-PD-1/PD-L1 treatment, or any unresolved irAE > grade 1; Note: previous immune-related ocular toxicity of any grade is excluded
• DOSE EXPANSION COHORT: Subjects who are receiving an immunosuppressive treatment for any reason, including chronic use of systemic steroid or prednisone equivalent at doses >= 10 mg/day within 14 days prior to the first dose of study treatment; use of inhaled or topical steroids or systemic corticosteroids < 10 mg is permitted
• DOSE EXPANSION COHORT: Subjects who have had prior radiotherapy within 2 weeks of therapy; subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis
• DOSE EXPANSION COHORT: Patient has received chemotherapy within 3 weeks prior to entering the study or has not recovered sufficiently (i.e., greater than grade 1, PI will judge patient recovery status) from adverse events due to agents administered more than 3 weeks earlier; exceptions are stable chronic toxicities not expected to resolve, such as peripheral neurotoxicity, alopecia, and fatigue
• DOSE EXPANSION COHORT: Prior monoclonal antibody within 4 weeks before study day 1 or not recovered (=< grade 1 or at baseline) from AEs due to agents administered more than 4 weeks earlier; exception to this rule would be use of denosumab
• DOSE EXPANSION COHORT: Brain metastases: symptomatic, unstable, or disease requiring use of steroid treatment
• DOSE EXPANSION COHORT: Subjects with any active or inactive autoimmune process (eg, rheumatoid arthritis, moderate or severe psoriasis, multiple sclerosis, inflammatory bowel disease, etc.) or who are receiving systemic therapy for an autoimmune or inflammatory disease; exceptions include subjects with vitiligo, hypothyroidism stable on hormone replacement, controlled asthma, type I diabetes, Graves' disease, Hashimoto's disease, or with PI approval
• DOSE EXPANSION COHORT: Evidence of or any history of interstitial lung disease or active, noninfectious pneumonitis including symptomatic and/or pneumonitis requiring treatment
• DOSE EXPANSION COHORT: Hepatitis B virus (HBV) or hepatitis C virus (HCV) viremia or at risk for HBV reactivation; hepatitis B virus DNA and testing for HCV RNA must be undetectable; at risk for HBV reactivation is defined as hepatitis B surface antigen positive; patients who had curative treatment for hepatitis B are allowed in the study
• DOSE EXPANSION COHORT: Subjects with clinical condition where subjects may not tolerate immune mediated hepatotoxicity; this includes extensive liver metastasis, excessive intake of alcohol (male > 4 drinks/day, female > 2 drinks/day), and the use of acetaminophen > 2 gms/day; per epacadostat investigator’s brochure
• DOSE EXPANSION COHORT: History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• DOSE EXPANSION COHORT: Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• DOSE EXPANSION COHORT: Current use or anticipated need for treatment with any medications or substances that are inhibitors or inducers of CYP3A4
• DOSE EXPANSION COHORT: Known allergy or reaction to any component of either study drug formulation; any history of serotonin syndrome (SS) after receiving 1 or more serotonergic drugs
• DOSE EXPANSION COHORT: Pregnant or nursing. There is a potential for congenital abnormalities and for this regimen to harm nursing infants
• DOSE EXPANSION COHORT: Subjects receiving monoamine oxidase Inhibitors (MAOIs) or drug which has significant MAOI activity (meperidine, linezolid, methylene blue) within the 21 days before screening